Genetic Alliance Webinar on the FDA Guidances: Summary of Panelist Remarks
On November 6, 2006, Genetic Alliance hosted a webinar to discuss the FDA draft guidances on genetic testing. Representatives of government, research, clinical care, industry, and laboratories, including Mara Aspinall, Kathy Hudson, David Mongillo, Mike Watson, and Janet Woodcock, participated. To read the transcript of questions and answers presented during the webinar, click here. While many questions were addressed during the webinar, time did not permit panelists to address all questions. To view questions generated during the webinar with answers supplied by panelists after the event, click here.
The major points each panelist presented follow.
Presentation from Janet Woodcock, MD
FDA Deputy Commissioner of Operations
Introduction
- The mentioned guidances don’t just refer to genetic tests, but also to medical devices.
- The Medical Device Amendment of 1976 called for regulation of all medical devices, including general controls, registration enlisting, good manufacturing practices, and reporting of adverse events, setting the foundation for FDA having risk-based regulation by intended use.
- All in vitro diagnostic (IVD) devices must establish adequate analytical performance. They need to be accurate and have clinical importance, which is established by the FDA in the review process.
- It is important to describe a set of tests that have their own realm, known as laboratory-developed tests, which are developed for use in only one lab and the test is provided as a service (locally or broadly). This type of test is often called a “home-brew” test. This type of test is:
- well-established in practice, but has misperceptions of fairness that have created problems.
- not submitted for clearance by the FDA. This is viewed as not a level playing field.
- not subject to pre-market review, which leads to problems with validity.
- It is important to make distinction between CLIA regulating labs and FDA regulation of tests.
ASR Guidance
- Regulation of ASRs was developed to ensure the quality of reagents purchased by labs for use in laboratory-developed tests. The rule was published in 1997 in response to an increasing need for quality control over the reagents.
- The rule created an incremental increase in regulation by down-classifying some of the tools that allow the reagents to be used in lab-developed tests. Such tests were manufactured under GMP and, therefore, did not need full review by the FDA. (All medical devices are required to be manufactured under GMP.)
- There is an effort to create a safe-harbor for laboratory tests, but at the same time maintain their quality and assure transparency in labeling. Assuring transparency in labeling is achieved by making it clear that the labs are in charge of transparency, not the manufacturers of the reagent, because the reagent is only a component of the final laboratory-developed tests. A rule was put into place to have a regulatory structure around these reagents that are sold and used in laboratory-developed tests.
- There is confusion because many believe that ASRs are not medical devices. The preamble to the ASR rule pointed out that clinical labs that develop in-house tests are acting as manufacturers of medical devices and are subject to FDA jurisdiction under the Act.
- The FDA is not saying that laboratory developed tests are not medical devices, but that they are going to exercise enforcement discretion as long as the controls the FDA felt should be in place were in effect. But many individuals did not interpret our actions in this manner.
- The current landscape has problems with some entities going beyond the boundaries of the rules. For instance, some manufacturers promoted products as ASRs that were inconsistent with the ASR rules—slipping them under as ASRs so they would not be subject to FDA oversight.
- The ASR guidance is intended to clarify the definition of ASR the limitations in marketing ASRs and to make sure people understand the rules. It is not intended to eliminate legitimate lab-developed tests, but to ensure that labs take responsibility. The guidance points out that labs must be able to take responsibility for the design and validation of tests.
- ASRs vs. Tests: Class I exempt ASR doesn’t mean it is an exempt test. Lab developed tests that use ASRs are not, by extension, Class I exempt tests. Intended use is what drives exemption.
IVDMIA Guidance
- Relates to tests that include elements that are not standard ingredients of in-house tests. They:
- raise safety and effectiveness concerns
- do not fall within the scope of laboratory tests
- carve out a niche of emerging new type of tests (or devices) that do not fit the original parameters and are therefore subject to FDA regulation rather than enforcement
- In the guidance, the FDA is trying to define them. To fit the definition, the device:
- uses clinical data to empirically identify an algorithm and employ that algorithm to calculate a patient’s specific result—a classification index
- yields a result that cannot be interpreted without the help of the test manufacturer
- A key issue is of safety or effectiveness. The concern is that many indexes are used to make recommendations that are of great clinical importance to patients, but there is a lack of transparency in third-party interpretation.
- This is NOT a software issue and not a multivariate issue.
- These devices are in a different category than home-brew tests because regulation is risk-based, and even within the IVDMIA class, there is a great amount of range in the type of regulation that will be applied.
- The FDA is trying to perform regulatory functions in the least burdensome way.
Presentation from Kathy Hudson, PhD
Director of Genetics and Public Policy Center
- The number of genetic tests is increasing steeply, and the complexity and importance of them is increasing as well.
- We want quality in the form of labs performing the tests, analytic validity of the tests, clinical validity of the tests, quality of the individual reagents, quality of the claims that are made about the tests, and the relationship of those claims to what the test can actually do.
- Quality of testing depends on quality of oversight. (The ASR and IVDMIA guidances are just one thin slice.)
- CMS is responsible for the quality of genetic testing labs and the analytic validity of home-brew tests. However, oversight has been viewed as insufficient (calling for tailored standards). CMS also does not get into the clinical validity of the tests: This is where FDA comes in.
- The FDA has asserted authority over a sub-set (why are these tests unique and why start here?). The draft guidances are very much technology-based rather than risk-based.
- Many wonder about the FDA’s intention and if this is their only bite or if they have plans for further regulation. There is no signal as to what the FDA’s overall strategy might be, as stakeholders are getting confusing signals from the agencies, with CMS deciding not to proceed and FDA testing the waters.
- There are also procedural issues with an odd character to the release of the draft guidance, which was released without previous discussion with various stakeholders. It appears that the draft guidance has been enforced, and that could risk short-circuiting the process for public engage destabilize ment, the market, and have adverse effects to access to important tests.
- Our community must address not just these proposed guidances, but overall changes to help ensure that genetic tests are of high quality, while encouraging innovation and ensuring access to important tests.
- Ultimately, we must focus on transparency and encourage an oversight system that encourages and rewards transparency. Also, we need to level the playing field, rewarding innovation and ensuring access.
- We are at an interesting point in time with a lot of action in public policy on genetic testing. We need to focus on how all of this creates great opportunities for positive change.
Presentation from Mara Aspinall
President of Genetics at Genzyme
Innovation
- We want to continue innovation. For the first time in four years, a substantial influx of companies has come into the space of diagnostics. This is exciting for patients and has moved the industry. Over the last few years we have seen an increase in partnership between diagnostic companies and PhRMA companies, meaning diagnostics as an industry and product is more and more important. With this success come questions about the purpose and function of the tests. We must emphasize understanding of the impact of diagnostics and continuation of innovation.
- An example includes innovation with oncology in the form of hematological or blood cancers. The survival rate is close to 75% for these cancers, and there are many reasons why. One comes from better diagnosis and, with that, more focused drugs. This impacts patients and research. Lab-developed tests have had an important impact on this, and the current system helps bring the tests to market very quickly. Intellectual property is a piece of this, but not the only piece.
- We need a system that encourages diagnostic companies to perform their wares. We need the best and the brightest.
Reimbursement
- We need to ensure we have the rich world of diagnostics companies, labs, and research, and to think about what is happening in the full picture of rewarding innovation and ensuring that patients have the benefit. (We don’t want a drought in diagnostics.)
- Reimbursement should be appropriate to the value of research. If we focus on innovation, it has to start with a regulatory piece, then ensure reimbursement as such.
Presentation from Mike Watson, PhD
Executive Director at the American College of Medical Genetics
- Of fundamental interest is ensuring safe and effective tests and that the public has access to these tests.
- Of issue with the guidances is that they are overly general in their nature, and it is what isn’t being said that you don’t understand about what is and isn’t being regulated, which is problematic in these situations because certainly the guidances themselves are not very broad.
- A move within the FDA to begin to regulate labs is a very significant change and ought to have come in under the Administrative Procedures Act because it is substantive even though the FDA says the language has been such that they are able to enter this area safely. The perceptions of the lab community are different from the FDA.
- Another issue is that we don’t know what the specific problems are that we are trying to fix through the guidances.
- The general view is that intellectual property has not been the problem with genetic tests; the problem is that intellectual property has led to monopolized tests.
- There is also concern that as the FDA begins to enter the area, how will they identify the labs that they have never paid attention to? How does the word get out?
- Lab-developed tests are traditionally overseen by CLIA, and the FDA has regulated the manufacturing side. Little attention has been paid to the improvement of CLIA itself as a mechanism of potentially getting at some of the issues of concern, and we are worried that some of the improvements in CLIA have been slowed down by the FDA’s move to enter into the laboratory area as a specific area of regulation.
IVDMIA Guidance
- The general view is that we need to protect the public and ensure that those algorithms are adequately understood and open to public review and understanding.
- We recognize that we are moving into an area of big science and putting pieces of information into risk calculations. Prenatal analyte screening to come up with a risk calculation would be perceived as being under this guidance. However, the individual results can be independently interpreted. Primary focus of the guidance is on expression arrays, not genomic arrays (can be confirmed by looking at results).
ASR Guidance
- ASRs are critical reagents used in a lab-developed genetic test.
- A problem in how the guidance is written is that it seeks to eliminate any hint that the product used or the ASR itself is going to be used for a particular intended use. The manufacturers are not allowed to provide this to the labs. Because the majority of available ASRs are for rare diseases, the incentive to the manufacture to go through all the parts of the regulatory process could decrease.
- The risk of restricting access to these products could drive labs to more complex methodologies such as DNA sequencing, which would be more expensive and have more difficult quality argument.
- Innovation is another issue of concern. The potential for labs to be stuck in a regulatory circle during a stage of development is worrisome in regard to ensuring long-term access to these particular tests.
David Mongillo, MPH
VP for Policy and Legislative Affairs, American Clinical Laboratory Association (ACLA)
- ACLA fully agrees that genetic and molecular diagnostics have the opportunity to revolutionize the delivery of care by identifying disease before the advent of symptoms and by targeting the best therapy based on the individual patient characteristics.
- Over the past several years there has been considerable growth and acceptance of laboratory-developed testing (LDT), especially those laboratory-developed tests used in genetic and molecular testing, and as we have heard, the use of LDTs is an important and well-established practice.
- There's little question that LDTs have benefited physicians and their patients by making readily available new and innovative laboratory testing, which otherwise wouldn’t have been available or would only have been available after FDA premarket approval process.
- In addition to the FDA oversight, all laboratory tests are regulated under CLIA, a very comprehensive set of regulations, and in fact all genetic and molecular laboratory testing can only be performed in those clinical laboratories with the highest level of regulatory oversight. The genetic tests offered to identify rare diseases are performed as lab-developed tests.
- Because these tests are for rare diseases, their volume is low, and that is a major deterrent to any manufacturer to apply for FDA approval. This leaves laboratory-developed testing as the only pathway available to patients for these rare disease tests.
- We all recognize the value of lab-developed tests and their important role in healthcare delivery. It’s incumbent on all of us to engage with the FDA on the introduction of any new guidance or regulations for laboratory-developed tests so that these diagnostics can continue to keep pace with rapidly-evolving genetic testing breakthroughs and technology and so that there won’t be regulatory restrictions, obstacles, or redundancies in place that will slow innovation and restrict patient access to these important tests.
